Use of quantum-chemical parameters for forecasting antiradical (HO·) activity of related structures containing a cinnamic mold fragment. III. Chalcones, flavanones and flavones with phloroglucinic type of ring “A”

Full Text

INTRODUCTION

In nature, flavonoids with the phloroglucinic type of ring “A” [1–4] are the most common.

With reference to the previous reports [5, 6], this paper presents an interpretation of the quantum-chemical characteristics of chalcone, flavanone and flavone derivatives, characterized by a phloroglucinic type of ring (42 compounds in total) and having electron-donating substituents on ring “B”.

THE AIM of the article is to determine the effect of the hydroxy group in position 6’ of chalcone derivatives, which upon heterocyclization react to form the corresponding flavanones and flavones, on the quantum-chemical parameters; as well as the calculation of the free valence indices (Fµ) of the carbon atoms of the main conjugation chain to explain the reactivity of the compounds under study relative to the hydroxyl radical OH.

MATERIALS AND METHODS

The calculations of the listed above parameters with the use of the semi-empirical method PM7 (WinMopac 2016 program), have been carried out on a workstation with an Intel Xeon E5-1620 3.5 GHz processor, 20 GB of RAM.

RESULTS AND DISCUSSION

This report presents the data on the analysis of the quantum chemical characteristics of the structures presented in Table 1.

 

Table 1 – Chalcone, flavanone and flavone derivatives with a phloroglucinic type of ring A*

 

Bond numbers (Nµ), free valence indices (Fµ)

The reactivity of organic molecules is conveniently explained taking into account the free valence indices of the corresponding regions. There is a relationship between this parameter and the bond number [7]:

$F\mu =N_{max}-N\mu$

It is appropriate here to describe the physical meaning of the bond number in more details, because it is actually the sum of the orders of all the bonds adjacent to this atom [7].

The value of Nµ reflects the degree of saturation of a particular atom: the larger Nµ, the more saturated a particular atom is and, conversely, the lower the value of Nµ, the more pronounced is the tendency of a given atom to form new bonds.

The theoretical maximum of the sum of the bond orders should be 4.732, which is considered a constant value. It corresponds to the sum of the bond orders of a carbon atom bound by three σ-bonds and three π-bonds with neighboring atoms in the threemethylmethane biradical [8, 9].

 

 

It should be notified that by the value of Fµ one can judge the possibility of an addition reaction involving the compounds containing π-bonds: the higher Fµ, the more pronounced the activity of the addition of neutral particles. For values of Fµ>1, a radical mechanism will prevail in these reactions.

Tables 2–4 shows the numerical values of the free valence indices of carbon atoms of the main conjugation chain of the analyzed groups of compounds.

 

Table 2 – The values of the bond numbers (Nµ) and free valency indices (Fµ) on the C-1 → C-6 → C-7 → C-8 atoms of the main conjugation chain of the 2’,4’,6’-threehydroxychalcone derivatives. Fµ=N_max–Nµ

Ser.No.	Сarbons	С-1		С-2		С-3		С-4		С-5		С-6		С-7		С-8
	R	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ
1	R1=R2=R3=R4=H	3.813	0.919	3.851	0.881	3.835	0.897	3.853	0.879	3.813	0.919	3.858	0.874	3.848	0.884	3.779	0.953
2	R1=OH. R2=R3=R4=H	3.745	0.987	3.788	0.944	3.829	0.903	3.842	0.890	3.806	0.926	3.765	0.967	3.829	0.903	3.732	1.000
3	R1=OCH3. R2=R3=R4=H	3.766	0.966	3.780	0.952	3.838	0.894	3.837	0.895	3.820	0.912	3.790	0.942	3.861	0.871	3.828	0.904
4	R2=OH. R1=R3=R4=H	3.752	0.980	3.793	0.939	3.769	0.963	3.846	0.886	3.806	0.926	3.856	0.876	3.877	0.855	3.822	0.910
5	R2=OCH3. R1=R3=R4=H	3.746	0.986	3.796	0.936	3.767	0.965	3.847	0.885	3.804	0.928	3.857	0.875	3.875	0.857	3.823	0.909
6	R3=OH. R1=R2=R4=H	3.813	0.919	3.788	0.944	3.771	0.961	3.778	0.954	3.809	0.923	3.853	0.879	3.842	0.890	3.768	0.964
7	R3=OCH3. R1=R2=R4=H	3.815	0.917	3.782	0.950	3.772	0.960	3.775	0.957	3.809	0.923	3.829	0.903	3.839	0.893	3.765	0.967
8	R2=R3=OH. R1=R4=H	3.805	0.927	3.786	0.946	3.762	0.970	3.763	0.963	3.765	0.967	3.837	0.895	3.845	0.887	3.773	0.953
9	R2=OCH3. R3=OH. R1=R4=H	3.808	0.924	3.779	0.953	3.758	0.974	3.761	0.971	3.762	0.970	3.835	0.897	3.842	0.890	3.771	0.961
10	R2=OH. R3=OCH3. R1=R4=H	3.809	0.923	3.788	0.944	3.760	0.972	3.763	0.969	3.764	0.968	3.840	0.892	3.873	0.859	3.810	0.922
11	R2=R3=OCH3. R1=R4=H	3.805	0.927	3.779	0.953	3.750	0.982	3.765	0.967	3.757	0.975	3.835	0.897	3.840	0.892	3.768	0.964
12	R2=R3=R4=OH. R1=H	3.798	0.994	3.776	0.956	3.708	1.024	3.770	0.962	3.736	0.996	3.850	0.882	3.852	0.880	3.784	0.948
13	R2=R3=R4=OCH3. R1=H	3.729	1.003	3.776	0.956	3.692	1.040	3.768	0.964	3.721	1.011	3.854	0.878	3.874	0.858	3.820	0.912
14	R2=R4=C(CH3)3. R3=OH. R4=H	3.794	0.938	3.794	0.938	3.748	0.984	3.790	0.942	3.798	0.934	3.834	0.898	3.858	0.874	3.788	0.944

Note: * – Numbering of carbon atoms of the main conjugation chain is given in accordance with the numbers generated by the calculation programs

 

Table 3 – The values of the bond numbers (Nµ) and free valence indices (Fµ) on the C-1 → C-6 → C-7 → C-8 atoms of the main conjugation chain of 5,7-dihydroxyflavanone derivatives

No.	Carbon atoms	С-١		С-٢		С-٣		С-٤		С-٥		С-٦		С-٧		С-٨
	R	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ
1	R1=R2=R3=R4=H	3.829	0.903	3.849	0.883	3.844	0.888	3.85	0.882	3.828	0.904	3.840	0.892	3.838	0.894	3.827	0.905
2	R1=OH, R2=R3=R4=H	3.776	0.956	3.795	0.937	3.842	0.89	3.843	0.889	3.822	0.91	3.770	0.962	3.832	0.900	3.819	0.913
3	R1=OCH3, R2=R3=R4=H	3.780	0.952	3.801	0.931	3.842	0.89	3.842	0.89	3.828	0.94	3.792	0.940	3.839	0.893	3.817	0.915
4	R2=OH, R1=R3=R4=H	3.762	0.970	3.792	0.94	3.773	0.959	3.845	0.887	3.814	0.918	3.841	0.891	3.839	0.893	3.826	0.906
5	R2=OCH3, R1=R3=R4=H	3.757	0.975	3.795	0.937	3.77	0.962	3.846	0.886	3.813	0.919	3.842	0.890	3.837	0.895	3.827	0.905
6	R3=OH, R1=R2=R4=H	3.828	0.904	3.785	0.947	3.784	0.948	3.777	0.955	3.823	0.909	3.820	0.912	3.835	0.897	3.826	0.906
7	R3=OCH3, R1=R2=R4=H	3.830	0.902	3.779	0.953	3.785	0.947	3.774	0.958	3.824	0.908	3.817	0.915	3.835	0.897	3.828	0.904
8	R2=R3=OH, R1=R4=H	3.764	0.968	3.778	0.954	3.749	0.983	3.798	0.934	3.832	0.919	3.832	0.900	3.837	0.895	3.827	0.905
9	R2=OCH3, R3=OH, R1=R4=H	3.759	0.973	3.776	0.956	3.746	0.986	3.796	0.936	3.814	0.918	3.833	0.899	3.836	0.896	3.829	0.903
10	R2=OH, R3=OCH3, R1=R4=H	3.767	0.965	3.771	0.961	3.754	0.978	3.792	0.94	3.814	0.918	3.831	0.901	3.835	0.897	3.826	0.906
11	R2=R3=OCH3, R1=R4=H	3.782	0.950	3.767	0.965	3.76	0.972	3.779	0.953	3.82	0.912	3.824	0.908	3.835	0.897	3.829	0.903
12	R2=R3=R4=OH, R1=H	3.748	0.984	3.772	0.96	3.712	1.02	3.776	0.966	3.748	0.984	3.833	0.899	3.838	0.894	3.822	0.910
13	R2=R3=R4=OCH3, R1=H	3.739	0.993	3.767	0.965	3.69	1.042	3.769	0.963	3.722	1.01	3.841	0.891	3.837	0.895	3.831	0.901
14	R2=R4=C(CH3)3, R3=OH, R4=H	3.804	0.928	3.793	0.939	3.755	0.977	3.785	0.947	3.811	0.921	3.818	0.914	3.838	0.894	3.829	0.903

Note: * – Numbering of carbon atoms of the main conjugation chain is given in accordance with the numbers generated by the calculation programs

 

Table 4 – The values of the bond numbers (Nµ) and free valency indices (Fµ) on the C-1 → C-6 → C-7 → C-8 atoms of the main conjugation chain of 5,7-dihydroxyflavone derivatives

No.	Carbon atoms	С-١		С-2		С-3		С-4		С-5		С-٦		С-٧		С-٨
	R	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ	Nµ	Fµ
1	R1=R2=R3=R4=H	3.808	0.924	3.851	0.881	3.835	0.897	3.852	0.88	3.809	0.923	3.829	0.903	3.793	0.939	3.701	1.031
2	R1=OH, R2=R3=R4=H	3.759	0.973	3.785	0.947	3.832	0.9	3.837	0.895	3.807	0.925	3.724	1.008	3.782	0.950	3.712	1.02
3	R1=OCH3, R2=R3=R4=H	3.769	0.963	3.77	0.962	3.834	0.898	3.834	0.898	3.81	0.922	3.739	0.993	3.793	0.939	3.712	1.02
4	R2=OH, R1=R3=R4=H	3.745	0.987	3.798	0.934	3.771	0.961	3.848	0.884	3.797	0.935	3.837	0.895	3.798	0.934	3.707	1.25
5	R2=OCH3, R1=R3=R4=H	3.738	0.994	3.8	0.932	3.767	0.965	3.848	0.884	3.795	0.937	3.838	0.894	3.796	0.936	3.705	1.027
6	R3=OH, R1=R2=R4=H	3.805	0.927	3.789	0.943	3.769	0.963	3.774	0.958	3.805	0.927	3.798	0.934	3.787	0.945	3.694	1.038
7	R3=OCH3, R1=R2=R4=H	3.808	0.924	3.783	0.949	3.771	0.961	3.771	0.961	3.805	0.927	3.794	0.938	3.783	0.949	3.691	1.041
8	R2=R3=OH, R1=R4=H	3.746	0.986	3.784	0.948	3.742	0.99	3.794	0.938	3.796	0.936	3.820	0.912	3.793	0.939	3.700	1.032
9	R2=OCH3, R3=OH, R1=R4=H	3.738	0.994	3.781	0.951	3.738	0.994	3.793	0.939	3.796	0.936	3.819	0.913	3.790	0.942	3.698	1.034
10	R2=OH, R3=OCH3, R1=R4=H	3.749	0.983	3.788	0.944	3.746	0.986	3.79	0.942	3.796	0.936	3.816	0.916	3.789	0.943	3.697	1.035
11	R2=R3=OCH3, R1=R4=H	3.741	0.991	3.775	0.957	3.743	0.989	3.788	0.944	3.796	0.936	3.816	0.916	3.787	0.945	3.697	1.035
12	R2=R3=R4=OH, R1=H	3.737	0.995	3.776	0.956	3.709	1.023	3.771	0.961	3.732	1.0	3.825	0.907	3.797	0.935	3.705	1.027
13	R2=R3=R4=OCH3, R1=H	3.723	1.009	3.771	0.961	3.689	1.043	3.773	0.959	3.71	1.022	3.833	0.899	3.791	0.941	3.704	1.028
14	R2=R4=C(CH3)3, R3=OH, R4=H	3.785	0.947	3.794	0.938	3.742	0.99	3.787	0.945	3.79	0.942	3.795	0.937	3.777	0.955	3.689	1.043

Note: * – Numbering of positions in accordance with figures generated by settlement programs

 

Derivatives of 2’,4’,6’-threehydroxychalcones

In the absence of substituents on the B ring (compound 1x), the C-8 atom is characterized by the smallest value of bond number 3.799 (Fµ = 0.953); therefore, the attachment of the hydroxyl radical is most likely due to this position.

The bond numbers for C-1 and C-5 (3.813) with a free valence index of 0.919 for both atoms, are slightly larger. For the rest of the atoms C-2, C-4, C-6 and C-7, the values of Nµ are in the range of 3.850, with a value of Fµ from 0.881 to 0.884.

The introduction of a hydroxy group into the C-1 position of the “B” ring (compound 2x) helps to reduce the bond number of this atom to 3.745 (Fµ = 0.987 at a.e. +0.3426) compared to the same position for the unsubstituted ring B, where Nµ = 3.813 (Fµ = 0.919 with a.e. = –0.1183). In the same compound, C-8 has the smallest bond number (Nµ = 3.732, Fµ = 1.000, a.e = –0.3721), and at the C-6 atom Nµ = 3.765 (Fµ = 0.967, a.e = –0.2414).

Relatively low values of the bond numbers and free valence indices are characterized by positions C-2 and C-5, where Nµ are equal to 3.788 (Fµ = 0.944) and 3.806 (Fµ = 0.926). Replacing the OH group in C-1 by OCH₃ retains the indicated patterns at the C-1, C-2, C-5, C-6, and C-8 atoms (Table 2).

There is OH group in the C-2 position of compound 4x, and this contributes to a decrease in the bond number at the C-1 atoms (Nµ = 3.752, Fµ = 0.980, a.e = -0.2504), C-3 (Nµ = 3.769, Fµ = 0.963, a.e = –0.3068). At C-8, the value of Nµ is significantly lower (Nµ = 3.822, Fµ = 0.910, a.e = –0.3225) than at C-1 and C-3.

The methoxy group in position C-2 (compound 5x) contributes to a decrease in the bond number by C-1 (Nµ = 3.746, Fµ = 0.986, a.e = –0.2567) and C-3 (Nµ = 3.767, Fµ = 0.965 , a.e = –0.2964). As for the C-8 atom, here Nµ = 3.823 (Fµ = 0.909, a.e = –0.3575).

The hydroxy group in position C-3 (compound 6x) contributes to a significant decrease in the bond number (Nµ = 3.768, Fµ = 0.964, a.e = -0.3475) compared to other carbon atoms in the compound 6x. Rather low bond numbers are recorded for C-2 (Nµ = 3.788, Fµ = 0.944, a.e = –0.2618) and C-4 (Nµ = 3.778, Fµ = 0.954, a.e = –0.3219). In the case of OCH₃ in position C-3 (compound 7x), practically the same features as in 6x, are retained.

Two hydroxy groups or two methoxy groups (compounds 8x and 11x) in positions C-2 and C-3 have a competitive effect on the propenone fragment C-7 → C-8 → C-9. According to the σ-Taft constants of the substituents for the C-3-OH group, σ = –0.370, for OCH₃ σ = –0.268; for C-2-OH groups, σ = +0.127, for OCH₃ σ = +0.115 [10]. This type of substitution contributes to a decrease in Nµ to 3.763 and 3.765 (C-2 and C-3 di-OH), 3.765 and 3.777 (C-2 and C-3 di-OCH₃) at C-4 and C-5 atoms, respectively, ring “B”).

For compounds 9x and 10x, where 2-OH and 3-OCH₃ (2-OCH₃ and 3-OH) groups are presented, almost all Nµ and Fµ values are the same on all carbon atoms of the propenone fragment.

The most characteristic features are recorded in compounds 12x and 13x, where ring “B” is represented by the remainder of pyrogallol or its fully methylated derivative. This arrangement of hydroxy groups is characteristic of natural flavonoids – myricetin, tricetin and tricin [1, 2, 3], which are the most active antioxidants [10] with respect to OH radical. Atoms C-1, C-2, C-5, C-8 are characterized by approximately the same values of Nµ and Fµ for both 12x and 13x (Table 2).

There is a very important feature: the carbon atoms on the «B» ring, to which the electron-donating OH and OCH₃ groups are bound with, are characterized by a positive charge (C-1 for 2x and 3x; C-2 for 4x and 5x; C-3 for 6x, 7x, 8x, 9x, 10x, 11x, 12x and 14x; C-4 at 8x, 9x, 10x, 11x, 12x, 13x).Table 2 shows that the carbon atoms listed above, are characterized by rather high values of the free valence indices, however, the presence of a positive charge on these atoms precludes the addition of an electrophilic hydroxyl radical to them at the initial stage.

5,7-dihydroxyflavanone derivatives

Table 3 shows the values of Nµ and Fµ for the analyzed flavanones. Comparing them with similar characteristics for chalcones (Table 2), it can be notified that flavanones have bond numbers and, accordingly, free valence indices, not fundamentally different from those of chalcones.

In flavanones 12anone and 13anone on C-1, C-3, C-5 atoms, the values of Fµ are very close or equal to 1.0, which indicates the predisposition of the indicated positions of the ring “B” to the attachment, possibly, by the radical mechanism.

The values of the free valence indices of C-6, C-7 and C-8 atoms also indicate the ability of these atoms to addition reactions.

5,7-dihydroxyflavone derivatives

It should be notified that in this group of derivatives, the C-7 carbon atom is characterized by a positive Mulliken charge in all compounds, without exception.

There is a similar pattern for atoms C-2 (compounds 4, 5, 9, 10–13one), C-3 (compounds 6–12one and 14one) and C-4 (compounds 12one and 13one).

The presence of a positive charge on carbon atoms in these positions indicates that at the initial stage, the addition of an electrophilic hydroxyl radical to the listed carbon atoms is excluded.

At the same time, the C-8 position is characterized by such features as low bond numbers (Nµ = 3.689–3.712) in comparison with other carbon atoms in combination with rather high free valence indices (Fµ = 1.02–1.25) (Table 4). At the same carbon atom, the negative Mulliken charge is in the range from –0.4122 to –0.4508.

Thus, the C-8 position is the most probable center where the radical OH should join.

It is clear that the interaction of an attacking particle with a given carbon atom of the vinylene group will entail a redistribution of the electron plane, bond numbers, Mulliken charge and free valence indices. This, in turn, will lead to the formation of new nucleophilic centers, where the subsequent ·OH radical will join, and so on until the carbon atoms in the flavone transformation products become extremely saturated. Every time, this can be judged by the changing values of the bond numbers, free valence indices, as well as the charges of carbon atoms and their electron density.

Such an approach, in our opinion, predetermines a quantitative assessment of the ratio of the moles number of the OH radical to 1 mole of the initial flavone during their interaction.

Table 5 shows the comparative quantum chemical characteristics of C-8 atoms in the analyzed groups of chalcones, flavanones and flavones containing electron-donating substituents in the rings “A” and “B”. The choice of the compounds containing three -OH and -OCH₃ groups (pyrogallol type of substitution) is determined, first of all, by their greatest antioxidant and anti-inflammatory kinds of activity, which was experimentally proved [10–12].

 

Table 5 – Comparative quantum-chemical characteristics of the C-8 atom of 2’-hydroxy-, 2’, 4’-dihydroxy- and 2’,4’,6’-threehydroxychalcones derivatives containing substituents in positions 3, 4, 5 of the ring “В”*

 

It follows from the table that, when passing from chalcones to flavones, the bond numbers (Nµ) decrease, which entails an increase in the values of the free valence indices (Fµ). That indicates an increase in the reactivity of the C-8 atom with respect to the electrophilic hydroxyl radical.

CONCLUSION

The article is devoted to the analysis of the quantum-chemical parameters of chalcones, flavanones and flavones, in which the “A” ring is represented by the phloroglucinic type, and the “B” ring of all the three groups of compounds in the same positions, contains electron-donating –OH and –OCH₃ groups.

In all the three compounds ‒14x, 14anone and 14one – the “B” ring contains two tert-butyl substituents and a phenolic hydroxyl between them (see Table 1), i.e. the “B” ring is a spatially hindered phenol which, due to the homolytic cleavage of the OH bond, is able to form a stable phenoxyl radical that actively interacts with the hydroxyl radical.

For the carbon atoms of the main conjugation chain C-1 → C-6 → C-7 → C-8, free valence indices (Fµ) have been found.

It has been established that the OH group in position 6′ of the “A” ring of chalcones, and in position 5 of the “A” ring of flavanones and flavones, has conflicting effects on the bond numbers: when passing from chalcone to flavanone, Nµ increases, and then, in flavone, sharply decreases. Using the dependence Fµ = Nmax – Nµ, the corresponding free valency indices have been found out; for the C-8 atoms of all flavone derivatives, they correspond to the expression Fµ≥1.

With reference to the previous reports and taking into consideration both the Mulliken charge (a.u.) and the electron density on this atom, the following conclusion has been confirmed: at the initial stage of the reaction the electrophilic hydroxyl radical is attached at the C-8 position of the cinnamoyl fragment.

FUNDING

This review did not have any funding from third-party organizations.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

AUTHORS’ CONTRIBUTION

E.T. Oganesyan – search and analysis of literature, interpretation of results, writing the text of the manuscript;

S.S. Shatokhin – search and analysis of literature, performance of quantum-chemical calculations, interpretation of the results

About the authors

Eduard T. Oganesyan

Pyatigorsk Medical and Pharmaceutical Institute - a branch of the Volgograd State Medical University

Author for correspondence.
Email: edwardov@mail.ru
ORCID iD: 0000-0002-2756-9382

Doctor of Sciences (Pharmacy), Professor, the Head of the Department of Organic Chemistry

Russian Federation, 11, Kalinin Ave., Pyatigorsk, Russia, 357532

Stanislav S. Shatokhin

Pyatigorsk Medical and Pharmaceutical Institute - a branch of the Volgograd State Medical University

Email: Shatohin.stanislav95@yandex.ru
ORCID iD: 0000-0001-7891-8338

postgraduate of the Department of Organic Chemistry

Russian Federation, 11, Kalinin Ave., Pyatigorsk, Russia, 357532

References

Supplementary files